Pancreatitis is an inflammatory disease of the pancreas with significant morbidity and mortality, and accounts for more than 300,000 hospitalizations annually in the United States alone at a cost of over $2 billion. There is no targeted therapy for the disease. Its pathophysiological mechanism is not clear. Pancreatitis in both its acute and chronic forms, causes severe pain that is often managed with narcotics, among them morphine, which, like its derivatives has been shown to affect the immune system and inflammatory pathways in a number of other diseases. However, the effect of morphine or its derivatives on modulation of progression of pancreatitis has never been studied. Our preliminary data, using an experimentally induced acute pancreatitis model and treatment with morphine after the onset of the disease, clearly indicate a significant increase in severity of locl and systemic injury. This is an interesting finding, which, if true, could have significant implications on the clinical outcome. Based upon these observations, we hypothesized that morphine exacerbates pancreatitis and associated systemic injuries, and causes delay in regenerative response in both acute and chronic forms of the disease. This is an exciting hypothesis, which we propose to test using three specific aims. The FIRST aim of our study will evaluate the effect of morphine and other opioids on injury and regeneration using three different experimental models of acute pancreatitis. This, while confirming previous observations, will also show whether the morphine effects are disease-specific rather than model- specific. In this aim, we will also confirm if the observed effect of morphine operates via the mu-opioid receptor. The proposed studies in the SECOND aim will look into the mechanism of morphine-mediated worsening of pancreatitis and the role of gut permeability using TLR2 and TL4 knockout mice. In this, based upon our preliminary data, we will specifically study how altered macrophage influx, switching of status and function affect pancreatic injury and its resolution. In the THIRD aim, we will evaluate the effect of morphine on chronic pancreatitis using two different experimental models with different mechanisms of action. We will investigate whether use of morphine promotes conversion of the recurrent acute form of the disease to the chronic form. Further, we will also study if morphine use to alleviate pain in chronic pancreatitis actually worsens the tissue damage, enhances fibrosis and hastens the destruction of the organ. If our results bear out in these studies, this would suggest that a seemingly benign supportive intervention like morphine is actually worsening the course of acute and chronic pancreatitis. The proposed studies have immediate clinical implication and have the potential to change the paradigm of treatment of acute and chronic pancreatitis.